The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells
The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells
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DOI：
10.4049/jimmunol.1201993
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发表时间：
2012-11-15
影响因子：
4.4
通讯作者：
Waisman, Ari
中科院分区：
文献类型：
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作者：
Reissig, Sonja;Hoevelmeyer, Nadine;Waisman, Ari
CyLD最初被认为是一种在家族性圆柱瘤病中突变的肿瘤抑制基因，这是一种常染色体显性遗传的皮肤多发性良性肿瘤，称为圆柱瘤。CyLD蛋白是一种去泛素化酶，通过与NEMO和TNFR相关因子2的相互作用，作为NF-kappa B和JNK信号的负调节因子。我们之前描述了一个新的小鼠品系，它只表达和过度表达自然发生的CyLD的一个剪接变体(CYLDex7/8)。在这项研究中，我们证明了CyLD在Treg的发育和功能中起着关键作用。CYLDex7/8小鼠T细胞具有高活性的表型，表现为炎性细胞因子的产生增加和NF-kB途径的结构性激活。此外，这些小鼠胸腺和外周器官中FoxP(3+)调节性T细胞的数量明显增加。重要的是，这些调节性T细胞显示CD25和CTLA-4的表达水平降低，这与抑制能力受损有关。因此，我们的数据强调了CyLD在维持T细胞动态平衡和正常的T调节细胞功能方面的重要作用，从而控制异常的T细胞反应。免疫学杂志，2012,189：4770-4776。
CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple benign neoplasms of the skin known as cylindromas. The CYLD protein is a deubiquitinating enzyme that acts as a negative regulator of NF-kappa B and JNK signaling through its interaction with NEMO and TNFR-associated factor 2. We have previously described a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLDex7/8). In this study, we demonstrate that CYLD plays a critical role in Treg development and function. T cells of CYLDex7/8 mice had a hyperactive phenotype manifested by increased production of inflammatory cytokines and constitutive activation of the NF-kB pathway. Furthermore, the amount of Foxp(3+) regulatory T cells in these mice was markedly enhanced in thymus and peripheral organs. Importantly, these regulatory T cells displayed decreased expression levels of CD25 and CTLA-4 associated with impaired suppressive capacity. Hence, our data emphasize an essential role of CYLD in maintaining T cell homeostasis as well as normal T regulatory cell function, thereby controlling abnormal T cell responses. The Journal of Immunology, 2012, 189: 4770-4776.